There is limited data to assess the true risk of unprotected oral-genital contact for acquisition of HIV infection. Animal data suggests direct inoculation of tonsil tissue with SIV results in a 100% transmission rate with a relatively low dose of virus. Observational cohort studies have demonstrated that the rate of oral transmission may be as high as 20-25% among men who have sex with other men, however there are no data for heterosexual oral-genital contact. This 4 year proposal is for 3 inter-related studies to 1) examine the attributable risk of oral-genital contact for transmission of HIV (and factors associated that may increase the risk), 2) study initial replication events in vivo, at the level of the mucosal surface, among persons with recent sexual exposure to HIV, and 3) develop an ex vivo model of oral transmission using humanoropharyngealtissue and primary isolates of HIV. The 1st study will enroll serodiscordant couples into a prospective, longitudinal 24 month follow-up study. Couples will be advised to abstain from all forms of unprotected sexual contact, however if they choose to have unprotected sex we will ask they limit it to oral-genital contact. Couples will fill out weekly sex diaries and have regular standadized dental examinations and laboratory monitoring of blood and semen to determine factors that might affect risk of oral-genital contact for HIV transmission. Analysis will be centered on number of people seroconverting by oral contact, the per contac risk, viral load in blood and semen of the source partner, epidemiologic parameters (smoking, flosing, dental appliances, etc.), and dental condition of the recipient (periodontal indicies, salivary flow rate, and mucosal integrity). The 2nd study will focus on patients refered for post sexual exposure prophylaxis (PSEP). Subjects will undergo mucosal swab and biopsy for analysis of duration of infectious HIV on the site of inoculation and tissue analysis by in situ hybridization and immunocytochemistry to determine which cell(s) are initially infected and the kinetics of viral replication at the time of dissemination. The 3rd study will be to develop an ex vivo model of oral transmission. Initial efforst will focus on separating cellular components of semen from uninfected donors and establishing methods of maintaining those cells in culture. Studies will be done to determine which of those cells are capable of harboring productive infection. We will then utilize human oropharyngeal tissues from uninfected persons obtained during routine surgical procedures (tonsilectomy, etc.) to determine which of those tissues can be infected from virus produced in the cell lines that have been established.